• Denitza P Blagev, Joseph R Arron, Prescott G Woodruff, Owen D Solberg, Edwin J Ostrin, Michael I Love, Jeffrey C Peng, Nirav R Bhakta, Margaret Solon, Andrea J Barczak, Lorna T Zlock, Walter E Finkbeiner, K Mark Ansel, and David J Erle.
• Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
• Am. J. Respir. Crit. Care Med.. 2012 Nov 15;186(10):965-74.

RationaleChanges in airway epithelial cell differentiation, driven in part by IL-13, are important in asthma. Micro-RNAs (miRNAs) regulate cell differentiation in many systems and could contribute to epithelial abnormalities in asthma.ObjectivesTo determine whether airway epithelial miRNA expression is altered in asthma and identify IL-13-regulated miRNAs.MethodsWe used miRNA microarrays to analyze bronchial epithelial brushings from 16 steroid-naive subjects with asthma before and after inhaled corticosteroids, 19 steroid-using subjects with asthma, and 12 healthy control subjects, and the effects of IL-13 and corticosteroids on cultured bronchial epithelial cells. We used quantitative polymerase chain reaction to confirm selected microarray results.Measurements And Main ResultsMost (12 of 16) steroid-naive subjects with asthma had a markedly abnormal pattern of bronchial epithelial miRNA expression by microarray analysis. Compared with control subjects, 217 miRNAs were differentially expressed in steroid-naive subjects with asthma and 200 in steroid-using subjects with asthma (false discovery rate < 0.05). Treatment with inhaled corticosteroids had modest effects on miRNA expression in steroid-naive asthma, inducing a statistically significant (false discovery rate < 0.05) change for only nine miRNAs. qPCR analysis confirmed differential expression of 22 miRNAs that were highly differentially expressed by microarrays. IL-13 stimulation recapitulated changes in many differentially expressed miRNAs, including four members of the miR-34/449 family, and these changes in miR-34/449 family members were resistant to corticosteroids.ConclusionsDramatic alterations of airway epithelial cell miRNA levels are a common feature of asthma. These alterations are only modestly corrected by inhaled corticosteroids. IL-13 effects may account for some of these alterations, including repression of miR-34/449 family members that have established roles in airway epithelial cell differentiation. Clinical trial registered with www.clinicaltrials.gov (NCT 00595153).

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